Atmospheric aging of tire rubber antioxidants forms complex mixtures that trigger inflammation in human macrophages

Antioxidants added to tires to prevent degradation have recently been recognized as emerging environmental contaminants. While their acute aquatic toxicity has raised concern, these compounds are also emitted to the atmosphere and can be associated with particulate matter (PM). On PM they can react heterogeneously with oxidants, producing a range of transformation products (TPs) with unknown impacts to human health via inhalation. Here, we show through laboratory experiments that many previously unrecognized TPs are formed in complex mixtures from both OH radical and ozone heterogeneous reactions of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and N,N'-diphenyl-1,4-phenylenediamine (DPPD). In the presence of nitrogen oxides, 13 TPs incorporated additional nitrogen atoms in the form of potentially toxic nitrosamines and nitramines. Overall, >150 TPs were detected in oxidation experiments, with > 88 also identified in ambient near-road and urban PM samples. When tested in human macrophages, these TP mixtures induced potent inflammatory responses and rapid cell death. The effects consistently exceeded those caused by the parent antioxidants and by the single quinone compound (6PPD-Q), commonly assumed to trigger toxicity, even at total mixture concentrations comparable to those recently measured in human blood serum. These findings suggest that atmospheric processing of tire-wear chemicals produces PM-associated transformation products, which could potentially contribute to an elevated risk of inflammation-driven diseases near roads. The work highlights the importance of evaluating atmospherically derived tire-wear TPs as dynamic, interactive mixtures rather than isolated compounds, particularly as electric vehicles with higher tire wear emissions become more prevalent.